The metabolism of arachidonic acid occurs by many pathways. One route of metabolism is via the cyclooxygenase (CO) mediated pathway which produces PGH.sub.2 which is in turn metabolized to the prostanoids (PGE.sub.2, TxA.sub.2, and prostacyclin). These products are produced by various cells including polymorphonuclear leukocytes, mast cells and monocytes. Another route is by the lipoxygenase mediated pathway which oxidizes arachidonic acid initially to 5-hydroperoxy-eicosatetraenoic acid (5-HPETE) which is further metabolized to LTA.sub.4, the precursor to the peptidoleukotrienes (LTC.sub.4, LTD.sub.4, and LTE.sub.4) and LTB.sub.4. Additionally 5-HPETE is converted to 5-hydroxyeicosatetraenoic acid (5-HETE).
Lipoxygenases are classified according to the position in the arachidonic acid which is oxygenated. Platelets metabolize arachidonic acid to 12-HETE, while polymorphonuclear leukocytes (PMNs) contain 5 and 15 lipoxygenases. It is known that 12-HETE and 5,12-diHETE are chemotactic for human neutrophils and eosinophils, and may augment the inflammation process. 5-HPETE is known to be a precursor to the peptidylleukotrienes, formerly known as slow reacting substance of anaphylaxis (SRS-A) and LTB.sub.4. The SRS family of molecules, such as leukotrienes C.sub.4 and D.sub.4 have been shown to be potent bronchoconstrictors. LTB.sub.4 has been shown to be a potent chemotatic for PMNs. The products of the 5-lipoxygenase pathway are believed to play an important role in initiating and maintaining the inflammatory response of asthma, allergy, arthritis, psoriasis, and inflammatory bowel disease. It is believed that blockage of this enzyme will interrupt the various pathways involved in these disease states and as such inhibitors should be useful in treating a variety of inflammatory diseases, such as those enumerated above. The absence of selective inhibitors of lipoxygenase, as opposed to cyclooxygenase, which are active in vivo has prevented adequate investigation of the role of leukotrienes in inflammation.
The arachidonic acid oxygenated products, as noted above, have been identified as mediators of various inflammatory conditions. The various inflammatory disease states caused by these mediators and many other conditions, as discussed herein, are all conditions in which an oxygenated polyunsaturated fatty acid metabolite inhibitor, such as a 5-LO inhibitor, would be indicated.
There remains a need for treatment, in this field, for compounds which are capable of inhibiting the oxygenation of arachidonic acid by inhibition of enzymes such as lipoxygenase, specifically 5-lipoxygenase (5-LO) thereby preventing the formation of various leukotrienes and prostaglandins.